Electroclinical features and phenotypic differences in adenylosuccinate lyase deficiency: Long-term follow-up of seven patients from four families and appraisal of the literature

Abstract

Objective: Adenylosuccinate lyase (ADSL) deficiency is a rare inherited metabolic disorder with a wide phenotypic presentation, classically grouped into three types (neonatal, type I, and type II). We aim to better delineate the pathological spectrum, focusing on the electroclinical characteristics and phenotypic differences of patients with ADSL deficiency.

Patients and methods: Seven patients, from four different families, underwent serial electroencephalogram (EEG), clinical assessment, and neuroimaging. We also performed a systematic review of the cases published in the literature, summarizing the available clinical, neurophysiological, and genetic data.

Results: We report seven previously unreported ADSL deficiency patients with long-term follow-up (10-34 years). From the literature review, we collected 81 previously reported cases. Of the included patient population, 58 % (51/88) were classified as having ADSL deficiency type I, 28% (25/88) as having type II, and 14% (12/88) as having neonatal. The most frequently reported pathogenic variants are p.R426H homozygous (19 patients), p.Y114H in compound heterozygosity (13 patients), and p.D430N homozygous (6 patients). In the majority (89.2%), disease onset was within the first year of life. Epilepsy is present in 81.8% of the patients, with polymorphic and often intractable seizures. EEG features seem to display common patterns and developmental trajectories: (i) poor general background organization with theta-delta activity; (ii) hypsarrhythmia with spasms, usually adrenocorticotropic hormone-responsive; (iii) generalized epileptic discharges with frontal or frontal temporal predominance; and (iv) epileptic discharge activation in sleep with an altered sleep structure. Imaging features present consistent findings of cerebral atrophy with frontal predominance, cerebellar atrophy, and white matter abnormalities among the three types.

Significance: ADSL deficiency presents variable phenotypic expression, whose severity could be partially attributed to residual activity of the mutant protein. Although a precise phenotype-genotype correlation was not yet feasible, we delineated a common pattern of clinical, neuroradiological, and neurophysiological features.

Keywords: ADSL deficiency; EEG patterns; epilepsy; genotype-phenotype correlation; monogenic diseases.

FIGURE 1

Electroencephalogram (EEG) and magnetic resonance imaging (MRI) evolution of Pt. 2. Panel I‐VI EEG of Pt. 2 from 12 months to 30 years of age (I) sleep EEG registration of Pt.2 (12 months year) shows hypsarrhythmia before the treatment with adrenocorticotropic hormone (ACTH); (II) awake EEG registration of Pt.2 after ACTH therapy shows a bilateral and symmetric 5–6 Hz background activity without epileptic discharges. (III) Awake EEG registration (13 years) showing high voltage, 1.5–2 Hz, spikes‐and‐waves predominantly over the frontal temporal regions. (IV) Awake EEG recording showing a disorganized background with spikes‐and‐waves predominantly on the frontal temporal regions and the start of a generalized seizure with clinical manifestations of staring spell and generalized stiffening. (V‐VI) Awake EEG (24 and 29 years) showing high voltage, bilateral spikes‐and‐spikes, and slow waves on frontal temporal regions only mildly reduced in frequency and amplitude over sequential controls. Pt. 2's MRI at 10 (A and B) and 19 years of age (C and D). (A) (inversion recovery, coronal plane) and B (T1, sagittal plane) show diffuse and generalized brain atrophy and ventriculomegaly with a thin and mildly dysmorphic corpus callosum. Cerebellar and vermian atrophy are also evident. Anterior commissure, optic nerves and olfactory bulbs were intact. (C and D) (T2, transversal plane) show a progression of brain atrophy, mainly in the frontal and temporal lobes (coherent with epileptic discharge localization), with areas of periventricular T2 hyperintensity. An analogous progression of EEG and MRI findings was documented for Pt.1.

FIGURE 2

Electroencephalogram (EEG) and magnetic resonance imaging (MRI) of Pts. 3 and 4. Panels I and II show the EEG of Pt. 3 and Pt. 4, respectively (both at 16 years): they display a common pattern of poor general organization, prevalence of diffuse theta activity, poor reactivity to eye closure, and rare spikes or spikes‐and‐waves with frontal predominance; poor sleep organization without recognizable sleep phases was also observed. Panel III (Pt. 3, 12 years) shows an EEG during sleep with sequences of spike‐and‐wave activation in sleep evolving as the patient grew. Panel IV shows a sleep EEG of Pt.3 at 17 years in a dedifferentiation between awake and asleep states, with no recognizable sleep figures. Pt. 3 Brain MRI (16 years). (A) T1 sequence, sagittal plane: we can observe a thin corpus callosum and brainstem. Cerebellar atrophy is also noticeable. (B) T2 sequence, coronal plane: cerebral atrophy with enlarged ventricles. (C and D) T2 sequence, coronal and horizontal plane: marked cerebral and cerebellar atrophy are evident.

FIGURE 3

Kaplan–Meier curves estimating survivals in different groups of patients. (A) Compares the different forms of the disease, showing lower survival rates in type N and I compared to type II patients. (B) Compares the most frequent variants observed in the sample, highlighting how lower survival is observed in p.Y114H heterozygous and p.R426H homozygous carriers. (C) Compares survival based on the age of onset, displaying how an earlier onset, not accounting for mutation type, was also associated with a poorer prognosis. (D) Compares the population of patients with epilepsy and the population without showing any statistically significant difference in terms of survival between the two population; however, we can notice a trend toward lower survival for patients with epilepsy.